The goal of this K24 application is to provide protected time for the candidate to conduct patient-oriented research and to expand her current program of mentoring. While the candidate has established a record of clinical research in neurodegeneration, she also has track record of advancing her mentees' careers and research as well. Recent studies have shown that mild cognitive impairment (amnestic MCI) and Alzheimer's disease (AD) patients have a lower concentration of amylin in plasma than the elderly who had normal cognition. In cross-sectional analyses, higher concentrations of plasma amylin are related to better cognitive function, especially in memory and executive domains. Amylin is a gut-brain axis hormone, which readily crosses the blood brain barrier (BBB) and mediates activities including regulating glucose metabolism, relaxing cerebrovascular structure and modulating inflammation, all of which could be beneficial for AD. From the Framingham Heart Study Offspring and Omni Generation 1 cohorts, we propose using plasma samples collected from 1995-1998 to relate to incident change in cognition and brain structure up to 15 years later. We posit that high levels of plasma amylin are protective for cognitive decline and brain atrophy in aging process. We have five specific aims including 1) studying the distribution of plasma amylin in FHS community based population; 2) determining the relationship between baseline plasma amylin and cognitive changes, including incident mild cognitive impairment and dementia; 3) examining the association between plasma amylin and changes in brain morphology; 4) stratifying these analyses by the presence of ApoE4 allele, diabetes and other vascular diseases and 5) studying the relationship between amylin, A, lipids, other gut- brain axis peptides and inflammation in FHS. Pramlintide is an amylin analog and an FDA approved drug for diabetes with a favorable safety profile in clinical use. Should we find that high levels f plasma amylin are protective for the incidence of AD; our study will provide additional rationale for a large phase 2 or 3 trial with pramlintide to determine if amylin type peptides can prevent and treat AD. We anticipate that this study may help open a new and unconventional avenue for the therapeutic of AD.